The present invention relates to the antagonism of the effects of melanin-concentrating hormone (MCH) through the melanin concentrating hormone receptor which is useful for the prevention or treatment of eating disorders, weight gain, obesity, abnormalities in reproduction and sexual behavior, thyroid hormone secretion, diuresis and water/electrolyte homeostasis, sensory processing, memory, sleeping, arousal, anxiety, depression, seizures, neurodegeneration and psychiatric disorders.
Obesity is a major cause and contributor to health problems such as type II diabetes, coronary heart disease, increased incidence of certain forms of cancer, and respiratory complications. It is a disease that is increasing at an alarming rate due to increased availability of high-fat diets, genetic susceptibility, and a more sedentary way of life in modern society. Obesity can be defined as weight gain resulting from a mismatch of energy intake and energy expenditure. Food intake and energy metabolism are regulated, in part, by the interaction of neuropeptides and their receptors. Recently, the role that the hormone leptin plays in controlling appetite has been elucidated.
Leptin is a peptide hormone produced by fat cells, regulating both food intake and and metabolism by acting on leptin receptors in the hypothalamus. Increased fat stores leads to increased secretion of leptin, resulting in a signal to the hypothalamus to decrease food intake, whereas decreases in adiposity result in lower leptin levels and a stimulation of food intake. Melanin-concentrating hormone (MCH) has been identified as an orexigenic peptide that counterbalances the activity of leptin.
MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incerta and lateral hypothalamus in response to both energy restriction and leptin deficiency. MCH is known to stimulate feeding when injected into the lateral ventricle of rats and the mRNA for MCH is upregulated in the hypothalamus of genetically obese mice (ob/ob) and in fasted control and ob/ob animals. Mice lacking MCH are hypophagic and lean with increased metabolic rate, whereas animals over-expressing MCH gain excess weight on both standard and high fat diets. MCH is thought to have effects on other nervous system functions as well (Nahon J L., The melanin-concentrating hormone: from the peptide to the gene. Crit Rev Neurobiol 8:221-262, 1994). An orphan G-protein coupled receptor (GPCR) was recently identified as a receptor for MCH.
Although there exists current pharmacologic therapies used to treat obesity, none of the current therapies achieve the U.S. Food and Drug Administration criteria for benefit measured by a 5% difference in mean weight loss, as weight loss efficacy is diminished by reduction of patient adherence to pharmacological therapy due to side effects of the drugs. Some of the side effects associated with current therapies include increased heart rate and blood pressure, and uncontrolled excretion of fat in stools. Thus, there exists a medical need for agents capable of preventing or treating eating disorders, weight gain and obesity, that at the same time, have improved efficacy and safety.
The present invention is directed to compounds of formula (I): 
or a therapeutically suitable salts, ester, prodrug or zwitterion thereof, wherein
R1, R2 and R3 are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy and RARBNxe2x80x94 wherein RA and RB are each independently a member selected from the group consisting of hydrogen and alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl and RCRDNcarbonyl, wherein RC and RD are independently a member selected from the group consisting of hydrogen, alkyl and aryl;
R4 is a member selected from the group consisting of hydrogen and alkyl;
R5 is xe2x80x94(CH2)mxe2x80x94Y-A-B;
m is from 0-6;
A is absent or is a member selected from the group consisting of alkoxyalkylene, alkylene and hydroxyalkylene;
B is a member selected from the group consisting of hydrogen, alkyl, aryl, arylC(O)xe2x80x94, arylS(O)2xe2x80x94, arylalkenyl, aryloxyalkyl, biaryl, biarylalkyl, cycloalkyl, heterocycle, heterocycleC(O)xe2x80x94, heterocycleS(O)2xe2x80x94, haloalkyl, RERFNxe2x80x94, RERFNC(O)xe2x80x94, RGSxe2x80x94 and RGOxe2x80x94;
RE and RF are each independently a member selected from the group consisting of hydrogen, alkyl, alkylC(O)xe2x80x94, aryl, arylalkyl, heterocycle, heterocyclealkyl, arylC(O)xe2x80x94 and arylS(O)2xe2x80x94;
RG is a member selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl and heterocycle;
Y is a member selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 and xe2x80x94S(O)2xe2x80x94, or is absent;
R6 is a member selected from the group consisting of hydrogen, alkyl and arylcarboxyalkyl; and
R7, R8, R9, and R10 are each independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and hydroxy or R7 and R8 taken together with the carbon atom that they are attached form oxo;
with the following provisos P1-P4:
P1 if Y is absent, m is 0 and if A is absent or is a member selected from the group consisting of alkoxyalkylene, alkylene and hydroxyalkylene,
then B is a member selected from the group consisting of hydrogen, alkyl, arylC(O)xe2x80x94, arylS(O)2xe2x80x94, arylalkenyl, aryloxyalkyl, biarylalkyl, cycloalkyl, heterocycle, heterocycleC(O)xe2x80x94, heterocycleS(O)2xe2x80x94, haloalkyl, RERFNxe2x80x94, RERFNC(O)xe2x80x94, RGSxe2x80x94 and RGOxe2x80x94; or
P2 if Y is xe2x80x94C(O)xe2x80x94, m is 0 and A is absent,
then B is a member selected from the group consisting of hydrogen, alkyl, arylalkenyl, aryloxyalkyl, cycloalkyl, heterocycle, haloalkyl, and RERFNC(O)xe2x80x94; or
P3 if Y is xe2x80x94C(O)xe2x80x94, A is absent and B is aryl or heterocycle,
then m is 1-6; or
P4 if Y is xe2x80x94C(O)xe2x80x94 and B is a member selected from the group consisting of arylC(O)xe2x80x94, arylS(O)2xe2x80x94, heterocycleC(O)xe2x80x94, heterocycleS(O)2xe2x80x94,
then A is a member selected from the group consisting of alkoxyalkylene, alkylene and hydroxyalkylene.
The present invention also provides a method of treating disorders mediated by MCH through the MCH receptor comprising administering a therapeutically effective amount of a compound of formula (II), 
or a therapeutically suitable salts, ester, prodrug or zwitterion thereof, wherein
R1, R2 and R3 are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy and RARBNxe2x80x94 wherein RA and RB are each independently a member selected from the group consisting of hydrogen and alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl and RCRDNcarbonyl, wherein RC and RD are independently a member selected from the group consisting of hydrogen, alkyl and aryl;
R4 is a member selected from the group consisting of hydrogen and alkyl;
R5 is xe2x80x94(CH2)mxe2x80x94Y-A-B;
m is from 0-6;
A is absent or is a member selected from the group consisting of alkoxyalkylene, alkylene and hydroxyalkylene;
B is a member selected from the group consisting of hydrogen, alkyl, aryl, arylC(O)xe2x80x94, arylS(O)2xe2x80x94, arylalkenyl, aryloxyalkyl, biaryl, biarylalkyl, cycloalkyl, heterocycle, heterocycleC(O)xe2x80x94, heterocycleS(O)2xe2x80x94, haloalkyl, RERFNxe2x80x94, RERFNC(O)xe2x80x94, RGSxe2x80x94 and RGOxe2x80x94;
RE and RF are each independently a member selected from the group consisting of hydrogen, alkyl, alkylC(O)xe2x80x94, aryl, arylalkyl, heterocycle, heterocyclealkyl, arylC(O)xe2x80x94 and arylS(O)2xe2x80x94;
RG is a member selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl and heterocycle;
Y is a member selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 and xe2x80x94S(O)2xe2x80x94, or is absent;
R6 is a member selected from the group consisting of hydrogen, alkyl and arylcarboxyalkyl; and
R7, R8, R9, and R10 are each independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and hydroxy or R7 and R8 taken together with the carbon atom that they are attached form oxo.
In particular, one such disorder mediated by MCH through the MCH receptor is obesity. Other disorders that are mediated by MCH through the MCH receptor are abnormalities in reproduction and sexual behavior, thyroid hormone secretion, diuresis and water/electrolyte homeostasis, sensory processing, memory, sleeping and arousal, anxiety and depression, seizure and in treatment of neurodegeneration or psychiatric disorders. Therefore the compounds of the present invention are useful in treating disorder such as obesity, abnormalities in reproduction and sexual behavior, thyroid hormone secretion, diuresis and water/electrolyte homeostasis, sensory processing, memory, sleeping and arousal, anxiety and depression, seizure and in treatment of neurodegeneration or psychiatric disorders. Accordingly, the present invention provides a method for treating obesity, abnormalities in reproduction and sexual behavior, thyroid hormone secretion, diuresis and water/electrolyte homeostasis, sensory processing, memory, sleeping and arousal, anxiety and depression, seizure and in treatment of neurodegeneration and psychiatric disorders comprising administering a therapeutically effective amount of a compound of formula (II).
According to another embodiment, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II) in combination with a pharmaceutically suitable carrier.